Our Program Project Grant (PPG) utilizes recent advances in chromatin biology, so-called epigenetics, to fundamentally increase our understanding of the long-lasting neural and synaptic abnormalities in the brain that underlie stimulant and opiate addiction. Our work focuses on key brain reward regions, nucleus accumbens (NAc) and areas of prefrontal cortex (PFC), which have been widely implicated in addiction. The PPG is composed of four Projects at three universities. The four PIs, Eric Nestler (Mount Sinai), Robert Malenka (Stanford), David Self (UT Southwestern), and Yasmin Hurd (Mount Sinai), are leaders in their fields who have an established history of effective collaboration and use their complementary expertise and approaches to chart a multidisciplinary course in the proposed research. Project 1 (Nestler) focuses on transcriptional and epigenetic changes induced in brain reward regions by self-administered stimulants and opiates. Project 2 (Malenka) mines those complex datasets to understand the molecular-cellular basis of neural and synaptic plasticity in brain reward neurons and how that plasticity influences circuit-level function. Projects 3 (Self) and 4 (Hurd) carry out parallel investigations into how this molecular and cellular pathology drives addiction-related behavioral abnormalities. Project 4 also validates these findings from animals in human postmortem brain tissue and thereby establishes the relevance of the basic research for human addiction. The PPG is supported by three Cores, an Administrative Core to oversee and coordinate PPG operations; an Animal and Molecular Models Core to provide animal models of addiction and the advanced tools (viral-mediated gene transfer, inducible mutations in mice, and optogenetics) to manipulate individual genes of interest or neural activity within limbic structures, and thereby provide causal evidence linking molecular-cellular-circuit plasticity to addiction-related phenomena; and a Chromatin and Gene Analysis Core to provide advanced state-of-the-art methods and bioinformatics to characterize genome-wide regulation of gene expression and chromatin modifications in addiction. This pioneering investigation of the molecular neurobiology of addiction will continue to help drive major advances in the field.